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Chemistry 328N

Lecture 15

March 8, 2016

More Carbonyl Chemistry

OR"

R R' C

OR"

+ H2O C R R'

O

2R"OH +

Chemistry 328N

Alcohols React with Aldehydes and Ketones in two steps…first

R R

O R'OH, H+

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Chemistry 328N

Hemiacetal reacts further in acid to yield an acetal

R OR'

OHR

R'OH, H+

Chemistry 328N

Example

O

OH HCl+

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Chemistry 328N

O H+ catalystOHHO

Diols Form ________

Chemistry 328N

Note that EVERY step is an equilibrium Therefore, the reaction can be pushed forward or backward by appropriate choice of conditions The forward reaction is synthesis The backward reaction is hydrolysis

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Chemistry 328N

Chemistry 328N

mechanism: reverse of acetal formation …hemiacetal is intermediate.

application: aldehydes and ketones can be "protected" as acetals.

Hydrolysis of Acetals

R1 OR'

OR'R2

H2O, H+

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Chemistry 328N

Hydrolysis

H3O+

Chemistry 328N

O OBr ???

+

OH O

HHH

Suppose you want to make this compound?

5-Hydroxy-5-phenylpentanal

Secret is….Acetals as protecting Groups

So…you got a problem with this plan ?????

It’s an alcohol. Use the Grignard Reaction!!

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Chemistry 328N

OBr H

H+ catalystOHHO

Br O

O+ H2O

Acetals as Protecting Groups l  If the Grignard reagent were prepared from 3-bromopropanal, it would self-destruct! l  First protect the -CHO group as an acetal

Chemistry 328N

Acetals as Protecting Groups l  Then do the Grignard reaction

Hydrolysis in dilute acid gives the desired product

Br O

O

O

Mg, THF

OH O

H

H

BrMg O

O

OMgBr

O

OH3O+

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Chemistry 328N

For example, the conversion shown cannot be carried out directly…..why?

CH CH3CCH2CH2C

O

C-CH3 CH3CCH2CH2C

O 1. NaNH2

2. CH3I

C: CH3CCH2CH2C

O –

because the carbonyl group and the carbanion are incompatible…….

Chemistry 328N

1) protect C=O 2) alkylate 3) restore C=O

Strategy

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Chemistry 328N

HOCH2CH2OH +

H2SO4, Cat.

benzene

CH3CCH2CH2C

O

CH

Protect

Chemistry 328N

1. NaNH2 2. CH3I

Alkylate

CH

H 2 C CH 2

O O

C

CH 3 CH 2 CH 2 C CH

H 2 C CH 2

O O

C

CH 3 CH 2 CH 2 C

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Chemistry 328N

H2C CH2

O O C

CH3 CH2CH2C CCH3

H2O

HCl

Deprotect

Chemistry 328N

Synthesis! Starting from benzene, cyclohexanone, and molecules with 3 carbons or less, synthesize the following molecule:

O

C C CCH3 C

HOO

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Chemistry 328N

Oxidation and Reduction

l  Aldehydes are oxidized to carboxylic acids by a variety of oxidizing agents and it is possible to do some selective reduction reactions

-4 -2 0 +2 +4

Oxidation

Reduction

C H 4 C H 3 O H H C H O

C O H O

H O C O

Chemistry 328N

Reduction l  Aldehydes can be reduced to 1° alcohols and

ketones to 2° alcohols. In addition, the C=O group can be reduced to a -CH2- group

Aldehydes Can be Reduced to Ketones

Can be Reduced to

O O OH

RCH RCH 2 OH

RCH 3 RCR'

RCHR'

RCH 2 R'

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Chemistry 328N

Metal Hydride Reduction l  The most selective reagents for the reduction of

aldehydes and ketones are NaBH4 and LiAlH4 –  both are sources of hydride ion, H:-, a very powerful

nucleophile

H ydride ion L ithium aluminum hydride (LAH)

Sodium borohydride

••

H

H H

H H-B-H H-Al-H Li + Na + H

Chemistry 328N

NaBH4 Reduction l  The key step in metal hydride reduction is transfer

of a hydride ion to the C=O group to form a tetrahedral carbonyl addition compound

B H H

H H C O

R

R

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Chemistry 328N

Closer look at borohydride reductions

B-O bond is much stronger than B – H Bond This is the driving force for the reaction…

Chemistry 328N

NaBH4 Reduction l  Reductions with NaBH4 are most commonly

carried out in aqueous methanol, in pure methanol, or in ethanol

R C H

O

+ N a B H 4 C H 3 O H

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Chemistry 328N

NaBH4

Examples: Sodium Borohydride

O

CH

O2N

methanol

O NaBH4

ethanol

Aldehyde

Ketone

Chemistry 328N

Lithium aluminum hydride

l  More reactive than sodium borohydride

l  Cannot use water, ethanol, methanol etc., as solvents

l  Diethyl ether and THF are the most commonly used solvent

l  This is a dangerous but useful reagent

LiAlH4

+ L i A l H 4 2 ) H 3 O + R C H 2 C C H 3

O

R C H 2 C C H 3

O H

H

1 ) T H F

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Chemistry 328N

Examples: Lithium Aluminum Hydride

Aldehyde

Ketone

O

CH3(CH2)5CH

1. LiAlH4 diethyl ether

2. H2O

O

(C6H5)2CHCCH3

1. LiAlH4 diethyl ether

2. H2O

Chemistry 328N

neither NaBH4 or LiAlH4 will reduce isolated double bonds

O

1. LiAlH4 diethyl ether

2. H2O

Selectivity

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Chemistry 328N

Selectivity in Reduction

l  LiAlH4 reduces any and all carbonyl compounds to the corresponding alcohols

l  NaBH4 only reduces aldehydes and ketone

Chemistry 328N

Catalytic Reduction

l  Catalytic reductions are generally carried out from 25° to 100°C and from 1 to 5 atm H2

l  Carbon-carbon double bonds can be selectively reduced using Rhodium catalysts

H2/RhO

NaBH4MeOH

OH

OO

O

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Chemistry 328N

Hydrogenolysis of benzylic carbonyls •  Palladium catalysis of hydrogenation reduces

only benzylic C-O bonds to methylene groups. •  Benzyl ethers, aldehydes and alcohols are also

reduced to the corresponding methylene group

O H 2 , P d / C

O

H 2 , P d / C